PROJECT SUMMARY/ABSTRACT The long-term objective of the proposed work is to understand how environmental and genetic factors interact to influence selective neuropathology. The work contained within this proposal focuses on the influence of manganese (Mn) exposure on the pathophysiology of Huntington's disease (HD). Mn over-exposure has been associated with changes in iron homeostasis and energy metabolism, and has been shown to promote the aggregation of intrinsically amyloidogenic proteins. Furthermore, a major site of Mn accumulation in the brain is the corpus striatum, which contains the neurons most vulnerable in HD. The chronic neurotoxic stress rendered by the mutant HD gene has been associated with alterations in iron homeostasis, deficits in cellular energy metabolism, and accumulation of the disease protein into amyloid-like inclusions. These similarities in the pathophysiology of HD and Mn neurotoxicity suggest a potential for Mn exposure to modulate HD neuropathology. Using pilot project resources provided by the National Institute of Environmental Health Sciences (NIEHS) Core Center in Molecular Toxicology at Vanderbilt University we tested the influence of increased Mn exposure on a striatal cell model of HD. These pilot experiments revealed a surprising and exciting result, that mutant HD striatal cells are resistant to Mn toxicity and pathophysiologically relevant exposures to Mn suppress mutant HD phenotypes. This proposal will utilize cellular and mouse models of disease to examine the molecular basis of this gene-environment neuroprotective interaction and evaluate the potential of Mn exposure to modulate HD pathogenesis. These studies are organized around three Specific aims. In the first of these we will define the contribution of specific HD protein domains and specific cellular mediators of Mn action to the Mn-HD gene-environment interaction by functional domain mapping and evaluating other metals with similar neurotoxic properties. In the second aim we will determine if Mn ions alter the conformational or functional properties of the HD protein by biochemical and biophysical protein assays utilizing cellular and animal models of HD. Then, in the third aim we will evaluate known pathological endpoints of Mn toxicity and HD neuropathology to elucidate the physiological processes that underlie the Mn-HD interaction in vivo. These specific aims are aligned with the mission of the NIEHS in that they examine the impact of a specific environmental toxicant on the pathophysiological processes of human disease. Finally, by exploring a gene-environment interface that moderates the onset and progression of HD, this study seeks to reveal mechanistic detail for how convergent genetic and environmental factors can enhance or suppress disease. PROJECT NARRATIVE With an aging population the personal, social and economic impact of neurodegenerative disease is rapidly escalating. Both environmental toxicants, such as manganese, and genetic insults, as in Huntington's disease, contribute to disease, but how genetic and environmental factors intersect to modulate disease is poorly understood. This proposal will examine an interaction discovered between manganese exposure and Huntington's disease that has the potential to moderate human disease, prioritize therapeutic targets, and provide insight into the basis of selective neuronal degeneration.